Treatment Of Relapsed And Refractory Dlbcl

More than half of all DLBCL patients initially entering remission with combination chemotherapy will relapse. The standard treatment approach for such patients is to deliver salvage chemotherapy followed by consolidative autologous stem cell transplantation in patients demonstrating chemosensitivity.71a Patients with chemorefractory disease and patients relapsing following an autologous stem cell transplant have an overall poor prognosis and should be considered for allogeneic stem cell transplantation or for clinical trials with investigational agents. The role of autologous and allogeneic transplant in the management of relapsed and refractory aggressive lymphomas is discussed elsewhere in chapters 64 and 65.

The optimal salvage regimen is not known, and there are no phase III, prospective, randomized trials comparing various combinations. Most of the data is from phase II trials, and the choice of treatment is often influenced by both patient features and physician preferences. Some commonly used regimens include DHAP,71a ESHAP71b (etoposide, methylprednisolone, cytarabine, cisplatin), ICE72 (ifosfamide, carboplatin, etoposide), IE73 (ifosfamide, etoposide), MINE73'74 (mesna, ifosfamide, mitoxantrone, etoposide) and EPOCH48 75 (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), among others. The DHAP regimen is one of the first salvage regimens to be designed. In the Parma trial, patients with relapsed lymphomas receiving DHAP had an overall response rate of 58%, but the 5-year EFS and OS of patients not subsequently transplanted were only 12% and 32%, respectively.71a

Ifosfamide-based regimens are gaining in popularity, partly due to the ability to dose-escalate the ifos famide, and also because they are excellent stem cell mobilizing regimens.7273 Overall response rates are over 60%, although the complete response rate is only 24%.73 The major advantage to improving salvage regimens is to demonstrate chemosensitivity, since this is arguably the most crucial characteristic-determining outcome following autologous stem cell transplantation in aggressive lymphomas. Of the ifosfamide-based salvage regimens for aggressive lymphomas, extensive data have been published on the ICE (ifosfamide, car-boplatin, etoposide) regimen developed at the Memorial Sloan Kettering Cancer Center (MSKCC).73-78 In an initial publication, investigators at MSKCC treated 163 consecutive transplant-eligible patients with relapsed or refractory aggressive NHL with 3 cycles of the ICE regimen. The overall response rate was 66%, allowing 89% of patients to proceed to a planned autologous stem cell transplant. There was minimal nonhematologic toxicity, although a third of patients had greater than grade 3 thrombocytopenia. All patients received growth factor support during each cycle of treatment. There are several other highdose ifosfamide-based regimens that are in widespread use,7273 and all appear to be effective at stem cell mobilization. However, despite high activity, none of these regimens are curative unless followed by a consolida-tive transplant procedure.

The addition of rituximab to salvage regimens appears to substantially improve the response rate. For example, Kewalramani and colleagues show that the overall response rate and complete response rate increases to 81% and 55%, respectively, when adding rituximab to the ICE regimen.79 Although not specifically demonstrated for large cell lymphoma, ritux-imab also serves as an "in vivo purge" during stem cell collection8081 and is likely to be an important component of most pretransplant salvage regimens for CD20-positive malignancies.

There are a multitude of promising investigational agents being pursued for the treatment of lymphomas. These include proteosome inhibitors (bortezomib or Velcade), anti-Bcl-2 agents (oblimersen sodium or Genasense), antiangiogenic agents, liposomal formulations of standard chemotherapeutic agents (liposo-mal vincristine, liposomal doxorubicin), newer monoclonal antibodies (epratuzamab), and radiolabeled monoclonal antibodies (ibritumomab tiuxetan or Zevalin, tositumomab or Bexxar). Phase II and III studies are ongoing, and several of the most active agents in preliminary studies are being incorporated into front-line regimens.

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